This paper presents the relative abuse risks of 11 prescription opioid compounds/formulations, both unadjusted as well as adjusted by the number of retail pharmacy-dispensed prescriptions for a particular high risk sample of substance abusers in treatment. Compound/formulation patterns of abuse via specific ROAs were also examined. Self-report data were drawn from nearly 60,000 substance abuse treatment patients who completed the ASI-MV Connect assessment at one of the 464 substance abuse treatment centers in the ASI-MV Connect network. In the present study, the unadjusted risks observed replicated the general findings of other studies. For example, Rosenblum and colleagues (2007) in their survey of prescription opioid and heroin abusers in methadone maintenance programs found that both groups reported highest abuse (ever and in past 30 days) of hydrocodone as well as ER and IR oxycodone at similar levels. These three were followed by methadone, morphine, hydromorphone and fentanyl. Although these authors did not distinguish ER from IR morphine, their relative ranking of the drugs maps well with the order found in this study (see Figure 3). The DAWN report  found a similar pattern of the six compounds on which they reported, such that oxycodone products were highest followed closely by hydrocodone, then methadone and morphine, with fentanyl having somewhat larger numbers than hydromorphone. The relative rankings of compounds and formulations observed here are also similar to those reported by Butler and colleagues (2008) who used ASI-MV Connect data collected between November 2005 and July 2008. Since the data used in this study are from 2009 only, it seems likely that the observed relative rankings are stable over time. Hydrocodone products were reported as most abused in the past 30 days, followed by ER and IR oxycodone products, methadone and ER morphine products, hydromorphone, IR morphine, ER fentanyl and IR fentanyl products. Finally, Kelly and colleagues (2008) looked at a very different population, namely a general public sample, and they used a household-based, telephone survey asking about any use (including legitimate use). These authors reported hydrocodone products to be more widely used than oxycodone products, again followed by methadone, with fentanyl and morphine at the same, lower level. Taken together, these results compare favorably with the present findings of relative risk of abuse based on unadjusted values observed in the present study. As these studies involve different populations, timeframes, and data collection methods, the general correspondence of findings suggest a certain robustness of the relative degree to which various prescription opioid compounds/formulations are used or abused in the US.
One goal of the present study was to go beyond the prior work to examine the effect on relative risks of abuse of prescription opioid compounds and formulations by adjusting for the number of prescriptions written in the local areas where the abusers reside. This question was stimulated in part by awareness that risk of abuse appears to be related to the prescribed availability within a community (e.g., ). Another major reason for investigating adjusted risks of abuse is the magnitude of differences between prescriptions for the different compounds and formulations. As can be seen in Table 3, the compound/formulation with the least amount of prescriptions in the patient home ZIP codes represented here (IR oxymorphone) has about 825 times fewer prescriptions than hydrocodone. This, in turn, raised the question of how relative risks of abuse of the prescription opioid compounds/formulations would change if level of prescribed availability were taken into account. It is not surprising that abuse risks are associated with prescription volume, since a drug must first be available before it can be abused. However, in practical terms, it may be helpful to examine the impact of prescription volume on abuse for particular compounds/formulations. From the prescriber's perspective, such an analysis may capture the extent to which a given prescription is likely to end up in the hands of an abuser. Consistent with this reasoning, the present study revealed clear differences in the impact of prescription volume on risk of abuse of the various prescription opioid compounds/formulations observed in the ASI-MV Connect data. As seen in Figure 3, the impact of prescription volume on abuse risks is largest for two of the most widely prescribed and widely abused compounds/formulations, hydrocodone and IR oxycodone. These drugs decline from the top of the ranking to the bottom after adjusting for prescription availability. This suggests that, despite the well-known high levels of abuse of these drugs, on a prescription-by-prescription basis, they are not as likely to be abused. Shifts in the other direction are seen for methadone and IR morphine, implying that the converse may be true for these drugs--namely prescriptions for these drugs may be more likely to end up being abused. Methadone, in this analysis, increased dramatically in abuse risk as did ER oxycodone. The risk of abuse of ER morphine increases slightly when adjusted for prescription volume. When considered together with IR morphine, this suggests a somewhat greater likelihood of abuse of any morphine product on a prescription-by-prescription basis. ER morphine, however, falls in the overall ranking from an unadjusted position of fifth drug abused to eighth in the analyses adjusted for prescription volume, behind several other, much less often prescribed compound/formulations (e.g., ER oxymorphone, IR oxymorphone, IR hydromorphone, and IR fentanyl). ER fentanyl (transdermal fentanyl), like ER morphine increases somewhat in absolute terms but is only above IR oxycodone and hydrocodone in the ranking of adjusted risk of abuse.
The finding of differential impact of prescribed volume on different prescription opioid compounds and formulations may have a variety of explanations. The large decline in the relative ranking of adjusted abuse risks for hydrocodone and IR oxycodone may be something of an artifact of the fact that these drugs are very widely prescribed and much more so than any of the other compound/formulations included in this study. Commonly prescribed for acute pain and minor surgery, these medications are likely to be found in many households in the US. When adjusting levels of prescription opioid abuse by prescription volume values with such large differences between the drugs compared, dramatic shifts in the adjusted levels may be expected. The low adjusted abuse risks of hydrocodone and IR oxycodone do not suggest that these drugs present less public health concern. Rather, we would conclude that, on a prescription-by-prescription basis, these drugs are comparatively less likely to be abused. In contrast to hydrocodone and IR oxycodone, many of the other opioid analgesics examined here are intended for and presumably prescribed for much smaller populations, such as chronic pain patients, and for specialized purposes such as breakthrough pain in highly opioid tolerant pain patients (e.g., IR fentanyl products). The adjusted risks for abuse suggest that these more difficult to obtain products (based on lower prescribed volume) are more abused in the ASI-MV Connect population than would be expected based on availability alone. This may suggest that these products are highly sought after and successfully obtained by the hard-core abusers represented in this treatment population. These data also suggest that a given prescription for one of these prescription opioids that are presumably highly desirable for abuse may be more likely to end up involved in abuse activity.
As noted in the Results section, methadone presents some unique challenges when compared directly with other prescription opioids. Current ASI-MV Connect screens for methadone present pictures and names of methadone preparations that come in pill or "wafer" forms. Almost half (44.5%) of the methadone abuse cases in this ASI-MV Connect sample indicated abuse of methadone by selecting only the "other not shown" category. Examination of 2010 data, where the ROA option of "drinking" is available, suggests that this option is chosen by the preponderance of respondents who select the other methadone option. This, in turn, suggests that these respondents may be using the solution or elixir formulation of methadone. Another issue regards the extent to which retail pharmacy volume as captured by the SDI Health data accurately depicts "prescription volume" for methadone in a way that is comparable to the other compounds and formulations examined here. Finally, given the use of methadone as a treatment modality in substance abuse treatment, it is difficult to know the extent to which respondents misidentified such use in the past 30 days as misuse. Examination of the data suggests that at least a quarter of respondents who indicated use of methadone as "other not shown" also indicated use by an alternate ROA, such as snorting or injecting. However, it is possible that those who are indicating they "swallowed" methadone are doing so as part of their treatment. The present configuration of ASI-MV Connect questions do not allow for a clear differentiation of individuals using methadone as part of their treatment. Changes in the screens are planned to allow for this differentiation in the future. For present purposes, however, the findings reported here regarding the impact of prescription volume on relative abuse risk estimates for methadone should be interpreted cautiously. These issues may be important considerations when evaluating the suitability of methadone as a candidate comparator for TRFs of other prescription opioid compounds. As illustrated in Figure 4, the relative standing of the prescription opioids presented without methadone reveals ER oxycodone as the compound/formulation with the greatest risk level after adjusting for prescription volume. In this Figure, the other compounds/formulations retain their relative positions with respect to ER oxycodone.
We also intended to describe different route of administration (ROA) patterns of the prescription opioids examined in this study. The findings here are consistent with those reported by Butler and colleagues (2008) who presented ROA patters for hydrocodone, oxycodone, morphine, methadone and fentanyl. These authors found hydrocodone to be mostly abused orally, oxycodone mostly abused nasally (by snorting or inhalation), morphine mostly likely injected, and fentanyl to be most likely smoked or "other." These findings are similar to the ones presented here, although the present analyses examine more compounds/formulations. In the present study, "oral ingestion" was more precisely broken down into swallowing whole (the "intended" route for all drugs except the fentanyl products) and chewing. The ASI-MV Connect now collects data on dissolving in mouth like a cough drop and drinking after dissolving in liquid, although these options were added in 2009 and not available for entire year examined here.
In the present study, it was clear that hydrocodone, IR oxycodone, and methadone had high levels of respondents (> .80 predicted probability) reporting swallowing the drug whole (intended ROA). Oxymorphone IR and ER had the highest levels of abusers reporting inhalation (prob. = .54 and prob. = .74 respectively) with abusers of ER oxycodone having a predicted probability of inhalation of about .44. As Butler et al. (2008) observed, morphine abusers tend to inject the drug, with IR morphine having a .56 predicted probability of injection and ER morphine at .45. Examination of the odd ratios comparing morphine (IR and ER) ROAs with all other drugs, highlights that morphine is significantly more likely to be injected than any other prescription opioid, with the exception of IR hydromorphone which had a predicted probability of injection of .55 (see "inject" column in Tables 6 and 7). Of note also is that IR morphine was significantly more likely to be injected than ER morphine. It is possible, given the consistency with patterns observed in earlier analyses  that the ROA patterns observed in this study are robust over time and reliably differentiate certain compounds/formulations. Such baseline information will be essential when evaluating TRFs of prescription opioid compounds. As noted above, TRFs are intended to inhibit efforts to modify the product to make its active ingredients available for alternative ROAs, such as snorting or injection. The extent to which a TRF can be determined to be successful will require a clear understanding of the ROA patterns characteristic of the TRF's parent drug or other comparators. Clearly, a TRF whose parent product is rarely injected will be unlikely to have a large impact on its use by that ROA. The present analyses are a step in the direction of delineating such ROA patterns for specific compounds and their ER/IR formulations.
There are several limitations of the present study. To begin with, important limitations of the ASI-MV Connect data should be highlighted. These data represent self-reports of persons entering treatment for substance use disorders. Self-report data are subject to recall bias or reluctance to report accurately. Despite this, it is unclear what other source of information about use and routes of administration can be reliably obtained. Over the years, research continues to support the reliability and validity of self-report of patients entering treatment (e.g., [38–43]). Although such literature generally supports the validity of self-report, it should be acknowledged that a few studies have found self-reported use to under-report drug use (e.g., [44, 45]). A further consideration is that individuals in this particular patient population have an acknowledged difficulty with substance abuse--a difficulty that has developed to the degree of necessitating treatment--and thus they may have less motivation to lie about their drug abuse in comparison with people who are not in treatment. In addition to the general support for the validity of self-reported substance use in the treatment setting, there is evidence that reporting via computer self-administration is as valid as reporting to a live interviewer. Where discrepancies exist, computer self-administration tends to elicit reports of more, rather than fewer, psychosocial and substance use problems . Finally, the ASI-MV Connect assessment uses a methodology for questioning respondents about use/abuse of particular prescription medications that is similar to methods employed by the NSDUH survey . NSDUH utilizes pictures of prescription products, names, slang and so forth as well as other widely accepted methodological practices for increasing the accuracy of self-reports, such as audio computer-assisted self-interviewing (as does the ASI-MV Connect). Examinations of these NSDUH methods have shown that they reduce reporting bias  in general populations.
Another limitation of the ASI-MV Connect data is that this dataset does not draw from a probability-based sample and, while having broad, national reach, does not provide comprehensive coverage of the US. The data collected by the ASI-MV Connect system are intended to provide sentinel population surveillance of substance abuse patterns in the US, but these data are yet to achieve national representativeness. The presented results are not nationally representative and are not intended to be used for estimating national incidence and prevalence rates. Furthermore, the population represented is not randomly selected. It consists of those who seek treatment for substance abuse and who have access to a substance abuse facility. The sample utilized is a convenience sample of patients assessed at treatment facilities that are part of the ASI-MV Connect network. The sample does not represent individuals who misuse or abuse prescription opioids but are not in treatment, nor does it include those in treatment but at treatment facilities not included in the ASI-MV Connect network, and the findings may not be generalizable to all patients with substance use disorders in treatment. Approximately 60% of cases in the ASI-MV Connect data (about 40% of the prescription opioid abusers--see Table 2) represent individuals whose treatment episode has been prompted by the criminal justice system. Thus, this database may have a socioeconomic bias against those who do not have access to such care.
These aspects of the ASI-MV Connect data serve as unavoidable limitations to any effort to establish population-based estimates. We believe, however, the present effort to examine relative risks of abuse and to describe abuse patterns observed in a saturated population, the ASI-MV Connect data may allow reliable estimates of large trends in abuse that would be relevant to the evaluation of TRFs and REMS. This is supported by the consistency with which the relative risks of abuse reported here and those reported in the other studies using different methods and populations, as mentioned above. Furthermore, the ASI-MV Connect dataset is the only source of data that provides systematic, prospective, and comprehensive information at the product-specific level necessary to answer questions regarding route of administration and other abuse patterns. Such information will be essential in addressing specific questions around tamper resistance and the effectiveness of REMS. Nevertheless, limitations of the data are acknowledged and present results should not be generalized beyond the population sampled. With this in mind, it should be noted that similar limitations apply to all public health data streams. Mortality data, for instance, suffer from underreporting and a lack of standardized procedures for attributing and coding poisoning deaths [48–50], yet these data have been used to support nationwide alerts from the FDA [51, 52].
On a final note, the evaluation of tamper resistance and the effectiveness of REMS will require analysis of a variety of available data streams. It is unlikely that any single data stream alone will capture all relevant data to necessary to adequately evaluate misuse and abuse of prescription opioids . Other methods, such as laboratory testing of abuse liability, could be particularly useful in evaluating tamper resistant properties of new formulations . However, the FDA has made clear that any product claims of abuse deterrence or tamper resistance would not be made without "long-term epidemiological data from community-based observational studies that document changes in abuse and addiction and the consequences of those behaviors" . Such epidemiological data will necessarily require samples of saturated populations such as those in substance abuse treatment and will need to obtain product-specific and route-specific data.
Finally, it is worth noting that while log-binomial models are recommended to estimate risk, these models are prone to either non-convergence or converging to invalid estimates (e.g., predicted probabilities greater than one) . As generally recommended, we monitored model convergence and confirmed that all predicted probabilities fell within the bounds of 0 and 1. Also, use of maximum likelihood estimation to fit logistic regression models tends to produce unreliable estimates when the number of events (or nonevents) is small for some categories (e.g. injection of IR fentanyl). As a result, very low predicted probabilities estimated from the random effects logistic regression model should be interpreted with caution. While exact logistic regression has been proposed for such scenarios, this approach was deemed infeasible and inappropriate since (1) several of the other categories were associated with a reasonably large number of events (e.g. injection of IR morphine) and (2) co-variation among observations due to repeated measures was present.